title: A 5-hydroxytryptamine receptor antagonist, sarpogrelate, reduces renal tubulointerstitial fibrosis by suppressing PAI-1.
abstract: A selective 5-hydroxytryptamine (5-HT) 2A receptor antagonist sarpogrelate (SG) blocks serotonin-induced platelet aggregation. It has been used clinically for the treatment of peripheral arterial disease. SG might be able to improve chronic ischemia, which contributes to renal fibrosis progression by maintaining renal microcirculation. This study investigated whether SG suppresses renal fibrosis. C57BL/6 mice fed a 0.2% adenine-containing diet for 6 wk developed severe tubulointerstitial fibrosis with kidney dysfunction. Subsequent SG treatment (30 mg·kg(-1)·day(-1)) for 4 wk improved these changes significantly by increasing peritubular blood flow in the fibrotic area, as evaluated by intravital microscopy and decreasing fibrin deposition. Urinary L-type fatty acid-binding protein, up-regulated by renal hypoxia, was also reduced by SG. Additionally, results showed that mRNA expression of plasminogen activator inhibitor-1 (PAI-1), which is known to promote fibrosis by mediating and enhancing transforming growth factor (TGF)-β1 signaling, was suppressed by SG treatment in the kidney. In vitro experiments using cultured murine proximal tubular epithelial (mProx) cells revealed that incubation with TGF-β1 and 5-HT increased PAI-1 mRNA expression; SG significantly reduced it. In conclusion, SG reduces renal fibrosis not only by the antithrombotic effect of maintaining peritubular blood flow but also by suppressing PAI-1 expression in renal tubular cells.
authors.affiliation: Dept. of Emergency and Critical Care Medicine, The Univ. of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan. kdoi-tky@umin.ac.jp.
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Hamasaki
authors.forename: Kent
authors.initials: K
authors.lastname: Doi
authors.forename: Rui
authors.initials: R
authors.lastname: Maeda-Mamiya
authors.forename: Emi
authors.initials: E
authors.lastname: Ogasawara
authors.forename: Daisuke
authors.initials: D
authors.lastname: Katagiri
authors.forename: Tamami
authors.initials: T
authors.lastname: Tanaka
authors.forename: Tokunori
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugaya
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
authors.forename: Eisei
authors.initials: E
authors.lastname: Noiri
mesh_terms: D000225:Adenine / Q000009:adverse effects; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D050556:Fatty Acid-Binding Proteins / Q000652:urine; D005355:Fibrosis; D066298:In Vitro Techniques; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D013386:Succinates / Q000494:pharmacology* / Q000627:therapeutic use; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C493320:Fabp1 protein, mouse; D050556:Fatty Acid-Binding Proteins; D017395:Plasminogen Activator Inhibitor 1; D012702:Serotonin Antagonists; D013386:Succinates; D053773:Transforming Growth Factor beta1; C064294:sarpogrelate; D012701:Serotonin; D000225:Adenine
keywords: L-FABP; PAI-1; peritubular blood flow; sarpogrelate; tubulointerstitial fibrosis